This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overexpression or activation of HER2 protein occurs frequently in breast, ovarian, and lung cancers. Blocking of HER2-mediated signaling with antibodies has shown to be effective in inhibiting cell growth. Our hypothesis is that peptidomimetics designed based on the structure of HER2-herceptin complex will inhibit the HER2-mediated signal for cell growth. By analyzing the crystal structure of the HER2 and its antibody (herceptin) complex, we have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. Two of the compounds, HERP5 and HERP7, exhibited antiproliferative activity with IC50 values of 0.390 mM and 0.143 mM respectively, against breast cancer cell lines. To increase the potency of HERP5 and HERP7, we have modified these molecules structurally. Computational docking methods were used to explore the interactions of various analogs of HERP5 and HERP7 with the HER2 protein extracellular domain. A total of 51 compounds were docked to the HER2 protein, and their binding modes were analyzed. Compounds that exhibited low docking energy were chosen for chemical synthesis and their biological activity was assessed. The anticancer effect of these compounds was evaluated in cell culture assays using BT474 and SKBR3 cell lines that overexpress HER2 protein and MCF-7 breast cancer cell lines that do not overexpress HER2 protein. The results indicated that peptidomimetics with a phenyl group in the R3 position exhibit potential antiproliferative activity. These results will be useful to extend our studies on the structure-activity correlation of novel anticancer agents and to understand the modulation of signals mediated by HER2 protein to target breast cancer.